Lin Jie, Niimi Yusuke, Clausi Mariano Guardia, Kanal Hur Dolunay, Levison Steven W
Department of Neonatology, Children's Hospital of Fudan University, Shanghai, China; Department of Pharmacology, Physiology, and Neuroscience, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA.
Department of Pharmacology, Physiology, and Neuroscience, Rutgers New Jersey Medical School, Newark, New Jersey 07103, USA.
Exp Neurol. 2020 Aug;330:113324. doi: 10.1016/j.expneurol.2020.113324. Epub 2020 Apr 19.
Neonatal hypoxic-ischemic encephalopathy remains the most important neurological problem of the newborn. Delays in diagnosing perinatal brain injuries are common, preventing access to acute therapies. Therefore, there is a critical need for therapeutic strategies that are beneficial when delivered beyond 24 h after birth. Here we show that Leukemia Inhibitory Factor (LIF) functions as an essential injury-induced neurotrophic cytokine in the CNS and that non-invasively administering LIF as late as 3 days after a hypoxic-ischemic insult improves neurological function. Using a mouse model of late preterm brain injury we show that astroglial and microglial/macrophage reactivity to hypoxia-ischemia was diminished at 3 days of recovery, but then exacerbated at 2 weeks of recovery in LIF haplodeficient mice. There also were significantly more CD68+/Iba-1+ cells in the ipsilateral striatum in LIF-Het mice compared to WT mice at 2 weeks of recovery. This desynchronized glial response was accompanied by increased neuronal cell death in the striatum and neocortex (Fluorojade C), hypomyelination (reduced MBP staining and thinner external capsule), increased extent of brain damage (Nissl) and diminished neurological function on sensorimotor tests. To our surprise, injured LIF-Het mice had ~7-fold higher IGF-1 levels than injured WT mice at 3 days after HI injury. Intranasally administered LIF activated the Jak-Stat-3 pathway both within the subventricular zone and the neocortex at 30 min after administration. When delivered with a delay of 3 days after the insult, intranasal LIF reduced the extent of brain injury by ~60%, attenuated astrogliosis and microgliosis in striatum, improved subcortical white matter thickness, increased numbers of Olig2+ cells in corpus callosum and improved performance on sensorimotor tests at 2 weeks of recovery. These studies provide key pre-clinical data recommending LIF administration as a neuroprotectant and regenerative cytokine and they highlight the feasibility of pursuing new therapeutics targeting the tertiary phase of neurodegeneration for hypoxic-ischemic encephalopathies.
新生儿缺氧缺血性脑病仍然是新生儿最重要的神经问题。围产期脑损伤的诊断延迟很常见，这使得无法获得急性治疗。因此，迫切需要在出生后24小时以上进行治疗仍有益的治疗策略。在此，我们表明白血病抑制因子（LIF）在中枢神经系统中作为一种重要的损伤诱导神经营养细胞因子发挥作用，并且在缺氧缺血性损伤后长达3天非侵入性给予LIF可改善神经功能。使用晚期早产儿脑损伤小鼠模型，我们发现，在恢复3天时，星形胶质细胞和小胶质细胞/巨噬细胞对缺氧缺血的反应性降低，但在LIF单倍体缺陷小鼠恢复2周时反应性加剧。在恢复2周时，与野生型小鼠相比，LIF杂合子小鼠同侧纹状体中CD68 + /Iba-1 +细胞也明显更多。这种不同步的胶质细胞反应伴随着纹状体和新皮质中神经元细胞死亡增加（Fluorojade C染色）、髓鞘形成减少（髓鞘碱性蛋白染色减少和外囊变薄）、脑损伤范围扩大（尼氏染色）以及感觉运动测试中神经功能受损。令我们惊讶的是，在缺氧缺血性损伤后3天，受伤的LIF杂合子小鼠的IGF-1水平比受伤的野生型小鼠高约7倍。鼻内给予LIF在给药后30分钟内激活了脑室下区和新皮质内的Jak-Stat-3信号通路。在损伤后3天延迟给药时，鼻内给予LIF可使脑损伤程度降低约60%，减轻纹状体中的星形胶质细胞增生和小胶质细胞增生，改善皮质下白质厚度，增加胼胝体中Olig2 +细胞数量，并在恢复2周时改善感觉运动测试表现。这些研究提供了关键的临床前数据，推荐将给予LIF作为一种神经保护剂和再生细胞因子，并且它们突出了针对缺氧缺血性脑病的神经退行性变第三阶段寻求新治疗方法的可行性。
